ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a very lethal form of cancer. While patient survival is highly dependent upon tumor stage, most patients already have advanced disease at the time of diagnosis due to the lack of clinical symptoms experienced by the patient until the tumor has progressed to a significant size. Also, there is a lack of both sensitive and specific imaging tests to detect early stage PDAC. Methods to detect PDAC at early stages are critically needed to improve the survival of patients with PDAC. While overall survival at diagnosis is only about 4-6 months, 30-40% of patients diagnosed at stage I disease can survive 5 years. The best currently available diagnostic test which is routinely performed in patients at high risk for PDAC is endoscopic ultrasound (EUS). However, EUS has low sensitivity and specificity and poor interobserver reliability for detecting small foci of PDAC. Combining EUS with molecular imaging capabilities (molecular CEUS) has the potential to increase our ability to detect early stage PDAC with high diagnostic accuracy. We have identified and validated a new biomarker, Thy1, which is differentially expressed in human PDAC but only minimally present in normal pancreas or chronic pancreatitis. Currently, we are developing a clinical grade Thy1-targeted contrast microbubble (MB) that allows detection of PDAC with high specificity in preclinical animal models. However, a barrier to the clinical translation of Thy1-targeted MB is the expected low concentration of targeted MB in small foci of early stage PDAC. This low concentration reduces our ability to visualize MB with conventional molecular CEUS imaging techniques because the signal to noise ratio (SNR) in tumors may not be high enough to differentiate small PDAC foci from background signal. This reduces our overall sensitivity to detect early stage PDAC. In this application, we propose to develop and test a high-sensitivity molecular CEUS imaging system using a combination of short-lag spatial coherence (SLSC) beamforming with Thy1-targeted MB. The SLSC beamforming technique utilizes the coherence characteristics of US signals to differentiate desired MB from those originating from background noise sources. This new beamforming technique will be implemented on a clinical US imaging system and tested and compared to conventional CEUS methods both in tissue mimicking phantoms as well as in a transgenic mouse model of PDAC development using Thy1-targeted MB. Because PDAC may arise in a setting of chronic pancreatitis, we will also test the SNR of molecular CEUS in PDAC on a chronic pancreatitis background. Molecular CEUS imaging signal will be correlated with histology and ex vivo quantitative immunofluorescence of Thy1 expression as reference standards. Successful completion of our research will result in a new Thy1-targeted molecular CEUS approach for early PDAC detection with improved SNR and specificity that can be further developed for clinical translation in the next phase of this research.